ABSTRACT Summary of Proposal This proposal describes a 5-year training and research plan that will allow Lisa Cranmer, MD, MPH to build on her background in global pediatric TB/HIV and molecular epidemiology and gain critical skills in immunology and advanced biostatistics. In order to become an independent investigator focused on understanding immune mechanisms to prevent TB in children with a unique niche in maternal-infant immunology, Dr. Cranmer will develop additional skills in: 1) humoral and innate immunology methods, 2) advanced longitudinal data analysis, and 3) vaccinology. Dr. Cranmer will leverage her substantive field research experience in Kenya using ongoing cohorts of mother-infant pairs and will receive close mentorship from researchers with over 30 cumulative years of experience performing molecular epidemiology studies and vaccine trials in high TB/HIV burden settings. Using these resources, Dr. Cranmer will develop the expertise to lead future TB vaccine trials in mothers and infants. Research Plan In TB-endemic settings, HIV-exposed uninfected infants have >20-fold higher risk of Mycobacterium tuberculosis (Mtb) infection compared to HIV-unexposed uninfected infants. Up to 40% of Mtb-infected infants develop TB disease with high morbidity and mortality. Current strategies to prevent Mtb infection in HEU infants, including BCG vaccination and primary isoniazid preventive therapy, have not been successful. In order to design new prevention strategies, Dr. Cranmer will evaluate the role of antibodies in protection of HEU infants from Mtb infection, and examine if maternal HIV exposure leads to changes in infant Mtb antibody-mediated innate immunity. Dr. Cranmer will evaluate if Mtb antibody levels or antibody-dependent cellular phagocytosis (ADCP)/antibody-dependent cellular cytotoxicity (ADCC) function in mother-infant pairs will confer protection against infant Mtb infection (Aim 1). She will then compare Mtb antibody-mediated immunity (e.g. antibody function and innate immune cytokine expression) to understand potential mechanisms of increased susceptibility to Mtb infection among Kenyan HEU infants (Aim 2). The proposed aims are designed to generate novel data that enhance our understanding of TB pathogenesis and inform development of innovative public health strategies to prevent infant Mtb infection, including new maternal and infant vaccines.